This invention relates to antibodies to human CD154 (CD154 being also known as gp39 or CD40-L) and to the use of such antibodies to inhibit an immune response mediated by CD154-positive cell interactions with CD40 positive cells, e.g in the treatment and/or prevention of diseases or disorders wherein CD154 interference with, modulation and/or inhibition of the CD154:CD40 interactions is therapeutically beneficial, e.g the prevention of cell, tissue or organ graft rejection, the prevention or treatment of autoimmune or inflammatory diseases, atherosclerosis or Alzheimer disease.
Cell-surface molecules which mediate contact-dependent helper-effector functions of T cells are important for inducing immune responses which require T cell help. For example, the interactions of CD154 on T cells with CD40 on B cells play a central role in activating B cell responses to antigens. It has also been shown that the inhibition of the interaction between CD154 and its receptor CD40 prevents T cell activation and may induce antigen-specific T cell or B cell tolerance. However CD154/CD40 interactions are not restricted to T and B cells or antigen-presenting cells (APCs).
Antibodies to CD154 have been proposed as agents blocking the CD154/CD40 interactions: two humanized anti-human CD154 monoclonal antibodies (MAbs) derived from mouse anti-human CD154 MAbs 5c8 and 24-31 are known. However there still exists a need for an effective method of modulating or blocking the CD154/CD40 interaction, e.g. in order to prevent or treat the disorders and diseases as herein indicated, for example to induce specific tolerance in allotransplantation, e.g. ideally by blocking co-stimulatory signals while at the same time allowing antigen-recognition and T cell receptor signalling.
We have now prepared improved antibodies to CD154 for use in the prevention or treatment of disorders, diseases or conditions as described hereinafter.